A large number of cytokines are known as humoral factors that are involved in the proliferation/differentiation of various cells and the activation of functions of differentiated mature cells as well as cell death. There are specific receptors for these cytokines, which are categorized into several families based on their structural similarities (Hilton D. J., in “Guidebook to Cytokines and Their Receptors” edited by Nicola N. A. (A Sambrook & Tooze Publication at Oxford University Press), p 8-16, 1994).
On the other hand, as compared to the similarities of their receptors, the homology of the primary-structure among cytokines is quite low. No significant amino acid homology has been observed, even among cytokine members that belong to the same receptor family. This explains the functional specificity of respective cytokines, as well as the similarities among cellular reactions induced by each cytokine.
Representative examples of the above-mentioned receptor families are the tyrosine kinase receptor family, the hemopoietin receptor family, the tumor necrosis factor (TNF) receptor family, and the transforming growth factor β (TGF β) receptor family. Different signal transduction pathways have been reported to be involved in each of these families. Among these receptor families, many receptors of the hemopoietin receptor family in particular are expressed in blood cells or immunocytes, and their ligands, cytokines, are often termed as hemopoietic factors or interleukins. Some of these hemopoietic factors or interleukins exist within blood and are thought to be involved in systemic humoral regulation of hemopoietic or immune functions.
This contrasts with the belief that cytokines belonging to other families are often involved in only topical regulations. Some of these hemopoietins can be taken as hormone-like factors, and representative peptide hormones, such as the growth hormone, prolactin, or leptin receptors, also belong to the hemopoietin receptor family. Because of these hormone-like systemic regulatory features, it is anticipated that administration of these hemopoietins can be applied to the treatment of various diseases.
Among the large number of cytokines, those that are presently being clinically applied include erythropoietin, G-CSF, GM-CSF, and IL-2. Combined with IL-11, LIF, and IL-12 that are currently under consideration for clinical trials, and the above-mentioned peptide hormones, such as growth hormone and prolactin, it can be envisaged that by searching novel cytokines that bind to hemopoietin receptors among the above-mentioned various receptor families, it is possible to find a cytokine that can be clinically applied with a higher efficiency.
As mentioned above, cytokine receptors share structural similarities among the family members. Using these similarities, many investigations are aimed at finding novel receptors. In particular, many receptors of the tyrosine kinase receptor family have already been cloned, using its highly conserved sequence at the catalytic site (Matthews et al., Cell, 65:1143-52, 1991). In comparison, hemopoietin receptors do not have a tyrosine kinase-like enzyme activity domain in their cytoplasmic regions, and their signal transductions are known to be mediated through associations with other tyrosine kinase proteins existing freely in the cytoplasm.
Though the sites on receptors binding with these cytoplasmic tyrosine kinases (JAK kinases) are conserved among family members, the homology is not very high (Murakami et al., Proc. Natl. Acad. Sci. USA, 88:11349-11353, 1991). Actually, the sequence that best characterizes these hemopoietin receptors exists in the extracellular region. In particular, a five amino acid motif, Trp-Ser-Xaa-Trp-Ser (SEQ ID NO:22), (wherein “Xaa” is an arbitrary amino acid), is conserved in almost all of the hemopoietin receptors. Therefore, novel receptors may be obtained by searching for novel family members using this sequence. In fact, these approaches have already led to the identification of the IL-11 receptor (Robb et al., J. Biol. Chem., 271:13754-13761, 1996), the leptin receptor (Gainsford et al., Proc. Natl. Acad. Sci. USA, 93:14564-8, 1996), and the IL-13 receptor (Hilton et al., Proc. Natl. Acad. Sci. USA, 93:497-501, 1996).